Separation of short lived alpha and beta emitting radionuclide daughter isotopes from long lived parent isotopes has been done for medical treatment, especially against cancer. The widespread recognition of the use of radiation to kill or neutralize unwanted cell growth such as cancer has led to increasing interest in various species of radionuclides. Of particular interest are radionuclides, such as .sup.213 Bi, which emit alpha radiation, or alpha emitters, because the alpha radiation emitted by these radionuclides does not penetrate deeply into tissue. .sup.213 Bi is normally produced as a daughter product of .sup.229 Th(t.sub.1/2 =7300 y). The radioactive decay chain in which .sup.213 Bi is found is well known: .sup.233 U(1.62.times.10.sup.5 yr t.sub.1/2) to .sup.229 Th to .sup.225 Ra(14.8 day t.sub.1/2) to .sup.225 Ac(10 day t.sub.1/2) to .sup.213 Bi 47 min t.sub.1/2). The daughters of interest for biological applications include .sup.225 Ra which decays to .sup.225 Ac. .sup.225 Ac in turn decays through a series of steps to .sup.213 Bi(t.sub.1/2 =45.6 m).
Briefly, by placing alpha emitters adjacent to unwanted cell growth, such as a tumor, the tumor may be exposed to the alpha radiation without undue exposure of surrounding healthy tissue. In many such schemes, the alpha emitter is placed adjacent to the tumor site by binding the alpha emitter to a chelator which is in turn bound to a monoclonal antibody which will seek out the tumor site within the body. Unfortunately, in many instances, the chelator will also bind to metals other than the desired alpha emitter. It is therefore desirable that the number of monoclonal antibodies bonded to metals other than the desired alpha emitter be minimized. Thus, it is desirable that the alpha emitter be highly purified from other metal cations. In addition, alpha emitters such as .sup.213 Bi(47 min t.sub.1/2) have very short half-lives. Thus, to utilize these short lived radionuclides effectively in medical applications, they must be efficiently separated from other metals or contaminants in a short period of time to maximize the amount of the alpha emitter available. Moreover, there exists low abundance, low energy Remissions associated with .sup.213 Bi that are useful for patient imaging. A more detailed description of the use of such radionuclides is found in numerous articles including Pippin, C. Greg, Otto A. Gansow, Martin W. Brechbiel, Luther Koch, R. Molinet, Jaques van Geel, C. Apostolidis, Maurits W. Geerlings, and David A. Scheinberg. 1995. "Recovery of Bi-213 from an Ac-225 Cow: Application to the Radiolabeling of Antibodies with Bi-213", Chemists' Views of Imaging Centers, Edited by A. M. Emran, Pleaum Press, New York, N.Y. (Pippin, 1995).
In 1996, Dr. David Scheinberg of the Memorial Sloan-Kettering Cancer Center, New York, N.Y., began administering .sup.213 Bi to a patient for treatment of acute leukemia. .sup.213 Bi is an alpha emitter which can be linked to a monoclonal antibody, "an engineered protein molecule" that when attached to the outside of the cell membrane--can deliver radioactive .sup.213 Bi, an alpha emitter with a half-life of 47 minutes. This initial trial represented the first use of alpha therapy for human cancer treatment in the U.S.
Various methods to separate bismuth from other radionuclides have been developed over the last few years. Recent work designed to develop Bi generators has focused on the use of an actinium-loaded organic cation exchange resin (Pippin, 1995; Wu, C., M. W. Brechbiel, and O. A. Gansow. 1996. An Improved Generator for the Production of Bi-213 from Ac-225, American Chemical Society Meeting, Orlando, Fla., August, 1996 (Wu, 1996); and Mirzadeh, S., Stephen J. Kennel, and Rose A. Boll. 1996. Optimization of Radiolabeling of Immunoproteins with Bi-213, American Chemical Society Meeting, Orlando, Fla., August, 1996). The major problem with the organic cation exchange method is that, with the need for larger amounts of ".sup.225 Ac cow" (&gt;20 mCi), the generator is limited by the early destruction of the actinium-loaded organic cation exchange resin. Attempts to minimize this destruction have been employed by Dr. Wu at the National Institute of Health (Wu, 1996) and Dr. Ron Finn (Finn, R., M. McDevitt, D. Scheinberg, J. Jurcic, S. Larson, G. Sgouros, J. Humm, and M. Curcio (MSKCC); M. Brechbiel and O. Gansow (NIH); M. Geerlings, Sr.(Pharmactinium Inc., Wilmington, Del.); and C. Apostolidis, and R. Molinet (European Commission, Joint Research Centre, Institute for Transruanium Elements, Karlsruhe, FRG.). 1997. "Refinements and Improvements for Bismuth-213 Production and Use as a Targeted Therapeutic Radiopharmaceutical", J. Labelled Compounds and Radiopharmaceuticals, XL, p. 293 (MSKCC, 1997)). Instead of loading the .sup.225 Ac as a "point" source on the top surface of a cation exchange column (Karlsruhe approach), the actinium is exchanged onto a portion of the organic resin in a batch mode. The loaded ion exchange beads are then mixed with non-loaded beads to "dilute" the destructive effect, when placed in an ion exchange column used for Bi separation. The .sup.213 Bi that is eluted from the generator is chemically reactive and antibody radiolabeling efficiencies in excess of 80% (decay corrected) are readily achieved. The entire process including the radiolabeling of the monoclonal antibody takes place at abient temperature within 20-25 minutes. The immunoreactivity of the product has been determined at a nominal value of 80%. The resultant radiopharmaceutical is pyrogen-free and sterile. However, under this approach, the preparation of the "cow" prior to separation of the Bi from the organic resin is time consuming and may not meet ALARA radiation standards. In addition, the .sup.225 Ac remains associated with the organic resin during the life time of the generator (.about.20 days) releasing organic fragments into the .sup.213 Bi product solution each time the "cow" is milked.
The Karlsruhe radionuclide generator described in Koch, 1997 was developed in support of Dr. David Scheinberg's (Memorial Soan-Kettering Cancer Center (MSKCC), New York, N.Y.) linking 213Bi to a recombinant humanized M195 (HuM195) antibody. All 225 Ac was loaded on an inlet edge of an AGMP-50 cation exchange resin column. Because of radiation damage to the ion exchange column and resin, MSKCC altered the Karlsruhe radionuclide generator to spread the 225Ac throughout the resin bed. This alteration reduced local radiation damage, but because the 225Ac is maintained in the resin, the resin does suffer damage from the alpha activity.
An inorganic ion exchange "generator" concept, has been developed by Gary Strathearn, Isotope Products Laboratories, Burbank, Calif. and is described (Ramirez Ana. R. and Gary E. Strathearn. 1996. Generator System Development of Ra-223. Bi-212, and Bi-214 Therapeutic Alpha-Emitting Radionuclides, American Chemical Society Meeting, Orlando, Fla., August, 1996 (Ramirez, 1996)). In this approach, inorganic polyfunctional cation exchangers are used to avoid damage from the intense alpha bombardment. A column of Alphasept 1.TM. is pretreated with nitric acid (HNO.sub.3), the .sup.225 Ac in 1M HNO.sub.3 feed is then loaded on to the column and the .sup.213 Bi product is eluted with 1M HNO.sub.3. The product HNO.sub.3 must then be evaporated to dryness to remove the nitric acid. It is then brought back into solution with a suitable buffered solution to prepare the final binding of the alpha emitter to a chelator and monocolyl antibody. The evaporation step extends the time required to prepare the final product and limits the usefulness of this approach.
An anion exchange bismuth separator and method was developed as described in U.S. patent application Ser. No. 08/789,973, now U.S. Pat. No. 5,749,042. The method requires hand operation of syringes and therefore has the disadvantage of needing technical labor with the inherent possibility of radioactive exposure to the laborer.
Because of the need for increasing amounts of therapeutic radionuclides, there is a need for a method of rapid and safe (low operator exposure) separation and purification of daughter radioisotopes from parent radioisotopes, for example .sup.213 Bi from .sup.229 Th.